Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss (20/200 or worse) among people in the United States aged 52 or older. AMD is the most common overall cause of blindness in the United States, Canada, Britain, and Australia. AMD is a degenerative disease of the macula, the area of the retina that is responsible for central vision and color perception. AMD tends to become worse with time and can best be described as a process of "wear and tear." Thus, the prevalence of severe visual loss increases with age. AMD encompasses several types of abnormalities that develop in the macula of older people. These abnormalities range from mild, with no loss of vision, to severe, with loss of all straight-ahead vision. Because the peripheral retina is unaffected by AMD, side vision is retained along with the ability to see in the dark. Most affected is the ability to see fine detail, to read, and to see well enough in the distance to drive.
The macula is the portion of the retina which lies directly behind the lens. The cones, light-sensitive cells which are responsible for central vision, are heavily concentrated in the macula. The peripheral retina is composed mainly of rods, the light-sensitive cells responsible for side and night vision. The macula is one hundred times more sensitive to detail than the peripheral retina. In a healthy macula, the clear layer of the retina on the inside of the eye is nourished and maintained by an adjoining layer called the pigment epithelium. Behind the pigment epithelium is the choroid which contains the blood vessels that transport nourishment to and carry waste material away from the retina.
There are three major forms of macular degeneration: dry (also known as atrophic), wet (also known as disciform, exudative, or neovascular), and pigment epithelial detachment. The dry form, which occurs in more than 85% of AMD patients, leads to gradual vision loss and can be a precursor to the wet form. The dry form results from an inability of the pigment epithelium to digest the cone tips that the retina produces as waste materials. The pigment epithelium may swell and die as a result of the collection of undigested waste materials. An early warning sign of dry macular degeneration is the formation of yellow spots, termed drusen, on the retina which result from the collection of undigested waste materials.
The wet form of macular degeneration, which occurs in about 10% of AMD patients, is associated with a sudden vision loss, resulting from the growth of new, abnormal blood vessels, also termed subretinal (choroidal) neovascularization (SRNV), under the pigment epithelium of the retina. The fluid and blood that leak from these new blood vessels cause the macula to bulge, resulting in distorted vision. As the disease progresses the cones are flooded and separated from their source of nourishment. Without nourishment, the cones degenerate and die, causing permanent blind spots. Pigment epithelial detachment, the third form of macular degeneration, may result with continued SRNV beneath the pigment epithelium, forcing it to detach from the choroid. Pigment epithelial detachment occurs in less than 5% of AMD patients.
Drusen, although used as an indicator of the development of macular degeneration, are currently not treated. Instead, patients with drusen are closely monitored through regular eye exams. At present there is no therapeutic or surgical treatment for the dry form of AMD. However, the dry form of AMD is accompanied by only gradual vision loss and the concomitant damage is usually not as severe, nor as sudden as, the damage associated with the wet form of AMD. Eyesight in patients with the dry form of AMD may be helped by special low vision spectacles or by learning to use side vision to accommodate for the loss of central vision. Because the dry form can lead to the wet form, patients are encouraged to monitor their vision using the Amsler Grid. This simple test can detect early retinal deformation caused by neovascularization associated with the wet form of macular degeneration.
At present there is no cure for AMD. The only treatment available for SRNV associated with the wet form of macular degeneration is laser photocoagulation. A narrow, highly focused beam of laser light is directed at the abnormal blood vessels. The heat produced by the laser dries up leaking blood vessels and inhibits further leakage, bleeding, and growth. However, laser treatment is effective only in selected classic cases, which include only about 25% of wet form patients (Bressler, N. M. (1990) Recent Advances in Management of Occult Age-Related Macular Degeneration, RPB Science Writers Seminar in Ophthalmology, Universal City, Calif.). Furthermore, patients treated with laser photocoagulation suffer a rapid and high rate of recurrence (10% within two months, 53% within three years following treatment). Laser treatment is also quite destructive and may result in irreversible damage to the retina. No therapeutic treatments are available for treating AMD, although current research has identified several drug candidates including: growth hormones, such as basic fibroblast growth factor (bFGF) and transforming growth factor .beta.(TGF-.beta.); neurotrophic factors, such as brain-derived neurotrophic factor (BDNF); regulators of neovascularization, such as plasminogen activator factor type 2 (PAI-2); anti-inflammatory drugs, such as dexamethasone; antioxidants; and forms of interferon, such as .alpha.-2a interferon.
All of the proposed therapies employ systemic injection of the drag candidate. However, preliminary studies using systemic injection of .alpha.-2a interferon have proven to be equivocal and in some cases deleterious due to marked side effects [Thomas and Ibanez (1993) Am J Ophthalmol 115(5): 563-8, Engler, et at. (1993) Acta Ophthalmol 71(1): 27-31, Loughnan, et at. (1991) Am J Ophthalmol 20(3): 173-5]. Clearly there is a need for a successful therapy for AMD. The subject invention provides such a therapy, providing for efficacious administration of the drug of choice by intraocular inoculation. The subject invention also provides a method whereby controlled intraocular release of the drug of choice is achieved over extended periods of time.